Expression of ecto-nucleoside triphosphate diphosphohydrolases-2 and -3 by the enteric nervous system impacts inflammation in experimental colitis and Crohn’s disease

Abstract
Background & Aims: Recent studies have suggested that the enteric nervous system can modulate gut immunity. Ecto-nucleoside triphosphate diphosphohydrolases (E-NTPDases) of the CD39 family regulate purinergic signaling by sequential phosphohydrolysis of extracellular ATP, a pro-inflammatory signaling molecule. Herein, we test the hypothesis that E-NTPDases modulate neuro-immune crosstalk in gut inflammation.
Methods: We determined expression patterns of NTPDase-2 and NTPDase-3 in murine and human colon. Experimental colitis was induced by dextran sodium sulfate (DSS) in mice deficient in NTPDase-2 or NTPDase-3. We compared plasma ADPase activity from Crohn’s patients to healthy controls, and correlated levels of ADPase activity with Crohn’s disease activity.
Results: NTPDase-2 and 3 were mainly expressed in cells of the enteric nervous system in both murine and human colon. When compared to wild type, DSS-induced colitis was exacerbated in NTPDase-2 null mice, as measured by both clinical disease activity and histology, while NTPDase-3 null mice merely developed more severe anemia. Colonic macrophages isolated from NTPDase-2 null mice displayed a more pro-inflammatory phenotype compared to wild type. Crohn’s patients had decreased plasma ADPase activity when compared to healthy controls. The enzyme activity sensitive to an inhibitor against NTPDase-2 and NTPDase-3 showed the most striking difference and was inversely correlated with Crohn’s disease activity.
Conclusions: NTPDase-2 and 3 are ecto-enzymes expressed in the enteric nervous system in both murine and human colon, and are protective against gut inflammation in experimental colitis and exhibit alterations in human Crohn’s disease. These observations suggest that purinergic signaling modulated by non-CD39 NTPDases governs neuro-immune interactions that are relevant in Crohn’s disease.